A Study of the Pharmacokinetics, Safety, and Efficacy of ASTX727 in Combination with Venetoclax in AML

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Taiho Oncology Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Jun 2022 → ongoing

Decision date (initial)

2024-08-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Taiho Oncology, Inc.

External identifiers

EU CT number

2024-516294-78-00

EudraCT number

2020-004772-18

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy, Pharmacokinetic

Phase I:
To evaluate the potential of drug-drug interaction: effect of ASTX727 on PK of venetoclax.
Phase 2 Part A:
- To evaluate clinical response with ASTX727 and venetoclax
combination therapy.
- To evaluate the potential of drug-drug interactions: effect of ASTX727 on PK of venetoclax.
Phase 2 Part B
- To evaluate clinical responsea with ASTX727 and venetoclax combination therapy.

Secondary objectives 11

1. Ph.1 To evaluate potential of drug-drug interactions: effect of venetoclax on PK of ASTX727
2. Ph.1 To evaluate the safety of ASTX727 and venetoclax combination therapy
3. Ph.1 To evaluate clinical response with ASTX727 and venetoclax combination therapy
4. Ph.1 To evaluate preliminary efficacy as determined by time-to-event endpoints with ASTX727 and venetoclax combination therapy
5. Ph.1 To evaluate secondary PK parameters of venetoclax, decitabine, and cedazuridine
6. Ph.2 Part A To evaluate the safety of ASTX727 and venetoclax combination therapy
7. Ph.2 part A To evaluate the potential of drug-drug interactions: effect of venetoclax on PK of ASTX727
8. Ph.2 Part A To evaluate composite clinical response rates with ASTX727 and venetoclax combination therapy
9. Ph.2 Part A To evaluate preliminary efficacy as determined by time-to-event endpoints with ASTX727 and venetoclax combination therapy
10. Ph.2 Part A To evaluate secondary PK parameters of venetoclax, decitabine, and cedazuridine
11. Ph.2 Part B Please refer to Protocol for sec objectives

Conditions and MedDRA coding

Acute Myeloid Leukemia (AML)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Participant must be 18 years of age or older
2. Histological confirmation of newly diagnosed AML by World Health Organization (WHO) 2016 criteria (Swerdlow et al 2017).
3. Projected life expectancy of at least 3 months.
4. Participants must be considered ineligible for intensive induction chemotherapy defined by the following: a) Age 75 years or older, or b) Age 18 to 74 years with at least one of the following comorbidities: i) Severe cardiac disorder (eg, congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina). ii) Severe pulmonary disorder (eg, diffusing capacity of the lung for carbon monoxide (DLCO) ≤65% or forced expiratory volume in 1 second [FEV1] ≤65%). iii) Creatinine clearance ≥30 mL/min to <45 mL/min. iv) Moderate hepatic impairment with total bilirubin >1.5 to ≤3.0 ×upper limit of normal (ULN). v) Phase 1: Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 (subjects with ECOG ≥3 are not eligible); Phase 2: ECOG Performance Status of 2 or 3 (subjects with ECOG 4 are not eligible).
5. For Phase 1, ECOG 0-2. For Phase 2, ECOG 0-3. Sex and Contraceptive Barrier Requirements
6. Participant can be male or female. Due to section size limitations, please refer to Protocol Section 10.2 for contraception requirements.
7. Capable of giving legally effective informed consent (as described in Appendix 1 [Section 10.1.3]), which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol, and willing to participate in the study.

Exclusion criteria 21

1. History of myeloproliferative neoplasm including myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia with or without BCR-ABL1 translocation and AML with BCR-ABL1 translocation.
2. The following karyotype abnormalities: t(8;21), inv(16) or t(15;17), or other acute promyelocytic leukemia variants that remain sensitive to all-trans retinoic acid (ATRA) therapy
3. Known active central nervous system involvement from AML.
4. Known human immunodeficiency virus (HIV) infection (due to potential drug-drug interactions between antiretroviral medications and venetoclax). Human immunodeficiency virus testing will be performed at Screening, only if indicated per local guidelines or institutional standards.
5. Known active hepatitis B or C infection (detectable viral load). Hepatitis B or C testing will be performed at Screening, only if indicated per local guidelines or institutional standards.
6. Severe hepatic impairment defined as: bilirubin >1.5×upper limit of normal (ULN) for subjects ≥75 years or >3×ULN for subjects <75 years; or aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) >3×ULN (unless abnormalities are considered to be due to leukemic organ involvement or bilirubinemia is due to known Gilbert's Syndrome).
7. Severe renal impairment defined as: calculated creatinine clearance or glomerular filtration rate <30 mL/min.
8. A malabsorption syndrome or other condition that precludes enteral route of administration
9. Cardiovascular disability status of New York Heart Association Class >2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue palpitations, dyspnea, or anginal pain.
10. Significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular or pulmonary disease, any other medical condition or known hypersensitivity to any of the study medications that in the opinion of the investigator would adversely affect his/her participating in this study.
11. Clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial, or fungal).
12. History of other malignancies prior to study entry, with the exception of adequately treated in situ carcinoma of the breast or cervix uteri; localized basal cell carcinoma or squamous cell carcinoma of the skin; previous malignancy confined and surgically resected (or adequately treated and controlled with other modalities); and any early stage malignancy for which no definitive therapy is required.
13. WBC count >25,000/μL. (Hydroxyurea treatment is permitted to meet this criterion.)
14. Treatment with the following: a) A hypomethylating agent (azacitidine or decitabine), or venetoclax including prior treatment for MDS. b) Chimeric Antigen Receptor (CAR)-T cell therapy. c) Investigational therapies for MDS or AML.
15. Participants who cannot discontinue concomitant prophylactic antifungal therapy with CYP3A inhibitor activity or other concomitant medications with moderate or strong CYP3A inhibitor activity ≥7 days or 5 half-lives, whichever is greater, prior to C1D1.
16. Participants who cannot discontinue concomitant drugs that are strong CYP3A or P-gp inhibitors ≥7 days or 5 half-lives, whichever is greater, prior to C1D1.
17. Participants who cannot avoid concomitant drugs known as moderate or strong CYP3A inducers
18. Current participation in another research requiring interventions such as drug therapy or study procedures
19. Known or suspected hypersensitivity to decitabine, cedazuridine, venetoclax, or any of their excipients
20. Known significant mental illness or other condition such as active alcohol or other substance abuse or addiction that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol.
21. Patients who consume grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit ≤7 days prior to C1D1

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Ph.1 Venetoclax AUC0-24 and Cmax on Day 5 with ASTX727 and Day 15 without ASTX727 in Cycle 2
2. Phase 2 Part A and B: CR rate
3. Phase 2 Part A: Venetoclax AUC0-24 and Cmax on Day 5 with ASTX727 and Day 15 without ASTX727 in Cycle 2.

Secondary endpoints 7

1. Phase I: Decitabine and cedazuridine AUC0-24 and Cmax on Day 5 with venetoclax and cedazuridine AUC0-8 and on Day 5 with venetoclax in Cycle 2.
2. Phase I, Phase II Part A and B: Incidence and severity of adverse events (AEs) as well as other safety assessments.
3. Phase I, Phase II Part A and B: • CR rate • CR+CRh rate • CR+CRi rate
4. Phase I, Phase II Part A and B: • Time to CR or CRh • Duration of CR or CRh • Overall survival
5. Phase I: • 5-day cumulative decitabine AUC in Cycle 2. • Decitabine AUC0-24 and Cmax on Days 1 and 2 in Cycle 2 • Cedazuridine AUC0-8 on Days 1, 2, and 5 in Cycle 2; AUC0-24, AUC0-inf, and Cmax on Days 1, 2, and 5 in Cycle 2. • Cmax, Cmin, Tmax, T1/2 and other secondary PK parameters.
6. Phase II, Part A and B: Decitabine and cedazuridine AUC0-24, Cmax, AUC0-8, and AUC0-inf on Day 5 with venetoclax in Cycle 2.
7. Phase II, Part A and B: Cmax, Cmin, Tmax, T1/2, and other secondary PK parameters.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Taiho Oncology Inc.

Sponsor organisation

Taiho Oncology Inc.

Address

101 Carnegie Center Suite 300

City

Princeton

Postcode

08540-6231

Country

United States

Scientific contact point

Organisation

Taiho Oncology Inc.

Contact name

Hamdy Elsayed

Public contact point

Organisation

Taiho Oncology Inc.

Contact name

Hamdy Elsayed

Third parties 7

Locations

1 EU/EEA country · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications